rs6702590

Variant names:

• chr1-201050977-A-G
• rs6702590
• NM_000069.3:c.4113+7T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-201050977-A-G
• chr1-201050977-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.4113+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,613,468 control chromosomes in the GnomAD database, including 412,372 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47269 hom., cov: 31)
  • Exomes 𝑓: 0.70 (365103 hom.)
• Consequence: CACNA1S NM_000069.3 splice_region, intron
• Scores: Splicing: ADA: 0.000007173
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.150
• Publications: 18 publications found

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

CACNA1S Gene-Disease associations (from GenCC):

• hypokalemic periodic paralysis, type 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• malignant hyperthermia, susceptibility to, 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital myopathy 18

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: SD, AD, AR Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-201050977-A-G is Benign according to our data. Variant chr1-201050977-A-G is described in ClinVar as Benign. ClinVar VariationId is 199680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000069.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	NM_000069.3	MANE Select	c.4113+7T>C		splice_region intron	N/A	NP_000060.2	Q13698

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.4113+7T>C		splice_region intron	N/A	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.4056+7T>C		splice_region intron	N/A	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.4053+7T>C		splice_region intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.779 AC: 118370 AN: 152036 Hom.: 47206 Cov.: 31

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.744

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.876

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.775

GnomAD2 exomes AF: 0.775 AC: 194789 AN: 251432 AF XY: 0.769

Gnomad AFR exome AF: 0.937

Gnomad AMR exome AF: 0.868

Gnomad ASJ exome AF: 0.745

Gnomad EAS exome AF: 0.996

Gnomad FIN exome AF: 0.762

Gnomad NFE exome AF: 0.669

Gnomad OTH exome AF: 0.756

GnomAD4 exome AF: 0.701 AC: 1024126 AN: 1461314 Hom.: 365103 Cov.: 45 AF XY: 0.705 AC XY: 512320 AN XY: 726970

African (AFR) AF: 0.941 AC: 31489 AN: 33480

American (AMR) AF: 0.865 AC: 38677 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 19407 AN: 26126

East Asian (EAS) AF: 0.983 AC: 39038 AN: 39696

South Asian (SAS) AF: 0.867 AC: 74770 AN: 86252

European-Finnish (FIN) AF: 0.758 AC: 40486 AN: 53420

Middle Eastern (MID) AF: 0.773 AC: 4448 AN: 5752

European-Non Finnish (NFE) AF: 0.658 AC: 731550 AN: 1111488

Other (OTH) AF: 0.733 AC: 44261 AN: 60378

GnomAD4 genome AF: 0.779 AC: 118493 AN: 152154 Hom.: 47269 Cov.: 31 AF XY: 0.786 AC XY: 58431 AN XY: 74338

African (AFR) AF: 0.929 AC: 38564 AN: 41520

American (AMR) AF: 0.802 AC: 12273 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 2581 AN: 3470

East Asian (EAS) AF: 0.994 AC: 5125 AN: 5156

South Asian (SAS) AF: 0.875 AC: 4223 AN: 4824

European-Finnish (FIN) AF: 0.770 AC: 8156 AN: 10596

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.666 AC: 45256 AN: 67974

Other (OTH) AF: 0.777 AC: 1641 AN: 2112

Alfa AF: 0.719 Hom.: 17212

Bravo AF: 0.790

Asia WGS AF: 0.928 AC: 3226 AN: 3478

EpiCase AF: 0.683

EpiControl AF: 0.670

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	not provided (2)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.18
DANN	Benign	0.54
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000072
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6702590; hg19: chr1-201020105;